CN109824537B - Preparation method of N- (3-acetyl-2-hydroxyphenyl) acetamide - Google Patents
Preparation method of N- (3-acetyl-2-hydroxyphenyl) acetamide Download PDFInfo
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Abstract
The invention relates to the technical field of organic synthesis and medicines, and provides a preparation method of N- (3-acetyl-2-hydroxyphenyl) acetamide, which takes 2-aminophenol as an initial raw material, and comprises the steps of performing amino acetylation and methylation of phenolic hydroxyl, then performing bromination on a benzene ring, introducing acetyl, and finally reducing and debrominating to obtain a target product, wherein the total yield is up to 41.7%, in the process of generating a compound E from a compound D, the compound D is subjected to ether bond breakage and can react with acetyl chloride to generate phenolic ester, and then, a rearrangement reaction is performed. The method has the advantages of wide and easily-obtained raw material sources, easily-realized industrialization of the route, less impurities, high yield and effectively improved purity of the target product.
Description
Technical Field
The invention relates to the technical field of organic synthesis and medicines, in particular to a preparation method of N- (3-acetyl-2-hydroxyphenyl) acetamide.
Background
Pranlukast (Pranlukast), also known as prussist, chemical name: n- [ 4-oxo-2- (1H-tetrazol-5-yl) -4H-1-benzopyran-8-yl]-4- (4-phenylbutoxy) benzamide; the molecular formula is as follows: c27H23N5O4(ii) a Molecular weight 481.50; CAS number: 103177-37-3; english chemical name: 4-oxo-8- (4- (4-phenylbutoxy) benzoylamino) -2- (tetra zl-5-yl) -4H-1-benopyran. The structural formula is as follows:
pranlukast (Pranlukast), a CysLTs receptor antagonist used for treating asthma and allergic rhinitis, is a novel anti-asthma drug marketed in the mid-nineties, and is one of three anti-leukotriene receptor antagonists which are currently of wide international interest.
The first leukotriene receptor antagonist in the world, originated by the japanese mini-fieldlayman, was first marketed in japan in 1995, and was clinically used mainly for the treatment of asthma and allergy, and also as an effective drug for the treatment of asthma.
N- (3-acetyl-2-hydroxyphenyl) acetamide is a primary intermediate of pranlukast, and the existing main synthetic route of N- (3-acetyl-2-hydroxyphenyl) acetamide is as follows: the p-hydroxyphenol is used as a raw material, and a final product can be obtained only through acetylation, rearrangement, debromination and acylation, so that the defects of long reaction route, high cost, large pollution and the like exist.
Disclosure of Invention
In view of the above problems in the prior art, the present invention provides a method for preparing N- (3-acetyl-2-hydroxyphenyl) acetamide.
The invention adopts the following technical scheme:
a preparation method of N- (3-acetyl-2-hydroxyphenyl) acetamide comprises the following steps:
the first step is as follows: synthesis of o-acetamidophenol (B)
Dissolving 2-aminophenol (A) in a solvent, dropwise adding acetic anhydride under the ice bath condition, wherein the molar ratio of the 2-aminophenol (A) to the acetic anhydride is 1:1-1.5, the unit millimole of the acetic anhydride corresponds to 2mL of ethyl acetate, after the reaction is completed, sequentially washing a reaction product with water, extracting with ethyl acetate, washing with brine, and drying with anhydrous magnesium sulfate to obtain a compound B, wherein the specific reaction formula is as follows:
the second step is that: synthesis of N- (2-methoxyphenyl) acetamide (C)
Adding o-acetaminophenol (B) and a phase transfer catalyst into a container, adding dimethyl carbonate, reacting under the conditions of heating and refluxing for 3-5 hours to obtain a compound C, wherein the specific reaction formula is as follows:
the third step: synthesis of N- (5-bromo-2-methoxyphenyl) acetamide (D)
Dissolving N- (2-methoxyphenyl) acetamide (C) and NBS in a solvent, reacting for 2-4h in ice bath under the protection of nitrogen to obtain a compound D, wherein the specific reaction formula is as follows:
the fourth step: synthesis of N- (3-acetyl-5-bromo-2-hydroxyphenyl) acetamide (E)
Mixing N- (5-bromo-2-methoxyphenyl) acetamide (D) and AlCl3Dissolving in a solvent, dropwise adding acetyl chloride under the ice bath condition, introducing nitrogen for protection, and reacting for a period of time at normal temperature or at elevated temperature to obtain a compound E, wherein the specific reaction formula is as follows:
the fifth step: synthesis of N- (3-acetyl-2-hydroxyphenyl) acetamide (F)
Adding N- (3-acetyl-5-bromo-2-hydroxyphenyl) acetamide (E) and Pd/C into a solvent, then dropwise adding an acid-binding agent into the solvent in a container, heating and introducing hydrogen, wherein the reaction temperature is 50-75 ℃, and the reaction time is 3-6h, so as to obtain a final product F, and the specific reaction formula is as follows:
furthermore, the phase transfer catalyst is cesium carbonate and potassium carbonate, and the reflux temperature range is 95-110 ℃.
Further, in the third step, a solvent is dichloromethane, ethyl acetate, DMF or chloroform, and after the reaction is completed, a 7% potassium carbonate solution and dichloromethane are added for extraction, and then, the mixture is dried over anhydrous magnesium sulfate.
Further, in the fourth step, N- (5-bromo-2-methoxyphenyl) acetamide (D), AlCl3The molar ratio of (1: 1.4) - (1.6), after the reaction is completed, adding ice water and dichloromethane for extraction, and sequentially using saturated NaHCO3Solution and brine washes, noneDried over sodium sulfate.
Further, in the fifth step, the acid-binding agent is selected from triethylamine, sodium bicarbonate, sodium carbonate, sodium hydroxide or sodium acetate, the weight ratio of the N- (3-acetyl-5-bromo-2-hydroxyphenyl) acetamide (E) to the Pd/C is 1:0.05-0.2, and the molar ratio of the N- (3-acetyl-5-bromo-2-hydroxyphenyl) acetamide (E) to the acid-binding agent is: 1:1-3, wherein the weight ratio of N- (3-acetyl-5-bromo-2-hydroxyphenyl) acetamide (E) to solvent is 1: 5-10; after the reaction is finished, cooling the reaction system, adding a mixture of ethyl acetate and toluene for recrystallization, stirring for a period of time under a reflux state, cooling, adding water to the product for washing, and cooling for crystallization.
Further, adding the product of the first step reaction into a solvent of ethyl acetate, and recrystallizing and purifying.
The invention has the beneficial effects that:
compared with the prior art, the method takes the 2-aminophenol as the initial raw material, the raw material is cheap and easy to obtain, the reaction condition is mild and easy to control, and the route is easy to realize industrialization; the preparation process provided by the invention optimizes the related method, greatly improves the reaction conversion rate, effectively improves the yield and purity of the target product, and reduces the production cost of the N- (3-acetyl-2-hydroxyphenyl) acetamide.
Detailed Description
The invention is described in detail below with reference to specific embodiments:
the synthetic route of the invention is as follows:
the following abbreviations have the meanings indicated below: NBS represents N-bromosuccinimide; AlCl3Represents aluminum trichloride; Pd/C represents palladium carbon; EA represents ethyl acetate; DMF means N, N-dimethylformamide; DMC represents dimethyl carbonate.
Example 1
The pranlukast original intermediate N- (3-acetyl-2-hydroxyphenyl) acetamide (F) is prepared as follows:
(a) synthesis of o-acetamidophenol (B)
109.13g (1moL) of Compound A was added to 2L of EA solvent under ice-bath conditions, 104mL (1.1moL) of acetic anhydride solution was added in portions, and after the addition, the temperature was slowly raised to room temperature, and the reaction was carried out for 2.5 hours. The reaction was checked for completion by thin layer chromatography, the reaction was washed with water, brine, dried over anhydrous sodium sulfate, concentrated to give an off-white solid and the product was recrystallized from EA solvent to afford compound B151.0 g in 99% molar yield.
(b) Synthesis of N- (2-methoxyphenyl) acetamide (C)
60.5g of compound B and 32.58g of cesium carbonate were dissolved in 3.2L of DMC at room temperature, and DMC was refluxed (substrate B and cesium carbonate in a molar ratio of 4:1, 6.26moL of cesium carbonate to 2L of DMC) at a reaction temperature in the range of 90-100 ℃ for 4h with stirring. And detecting the reaction by thin-layer chromatography, cooling the reaction solution after the reaction is completed, performing suction filtration, slowly pouring the filtrate into a small amount of water, extracting an organic phase by using EA, drying, and concentrating to obtain colorless oily matter C56.56 g, wherein the molar yield is 85%.
(c) Synthesis of N- (5-bromo-2-methoxyphenyl) acetamide (D)
Under ice-bath conditions, 58.5g (0.330moL) of NBS, 1L of dichloromethane, and 54.5g (0.33moL) of Compound C were sequentially added to a vessel, and the reaction was carried out under nitrogen atmosphere. After 3.5h of reaction, the reaction was checked by thin layer chromatography, and after completion of the reaction, the organic phase was extracted by adding 7% potassium carbonate solution and dichloromethane and dried over anhydrous magnesium sulfate to give a tan product D69.30 g with a molar yield of 86%.
(d) Synthesis of N- (3-acetyl-5-bromo-2-hydroxyphenyl) acetamide (E)
Under ice-bath conditions, 24.4g (0.1moL) of substrate D, 0.5L of dichloromethane, and 20g of AlCl were added in this order3(0.15moL) to a reaction flask, 10.5mL (0.15moL) of acetyl chloride was added dropwise, and after stirring for 5 minutes, the reaction was carried out at 25 ℃ for a while under nitrogen. Detecting the reaction by thin layer chromatography, adding ice water and dichloromethane for extraction after the reaction is completed, and saturated NaHCO3And brine, and finally dried over anhydrous sodium sulfate to give 21.43g of transThe molar yield of the reactant E is 78.8%.
(e) Synthesis of N- (3-acetyl-2-hydroxyphenyl) acetamide (F)
Adding 19g of reactant E, an ethanol solvent and triethylamine into a reaction bottle, stirring at room temperature for 0.5h, dissolving, adding Pd/C (5%, 0.5g), introducing nitrogen for several minutes to exhaust air in the container, then starting to introduce hydrogen (the gas velocity is controlled to be one bubble per second), raising the temperature to 50-75 ℃, and reacting for 3-6h, wherein the weight ratio of the reactant E to the Pd/C is 1:0.2, the molar ratio of the reactant E to an acid binding agent is 1:1, and the weight ratio of the reactant E to the solvent is 1: 5. Detecting the reaction by thin-layer chromatography, after the reaction is finished, stopping introducing air, cooling the solution, recovering Pd/C in filter residue, adding a mixture of ethyl acetate and toluene into the filtrate for recrystallization, stirring for 4 hours under a reflux state, filtering while hot, cooling for crystallization, washing the filter cake for 3 times by adding water, and drying to obtain 11.45g of a target product F with the molar yield of 85%.
In conclusion, the total yield of the target compound N- (3-acetyl-2-hydroxyphenyl) acetamide (F) was 41.7%, and the purity thereof was 99.8% by HPLC.
Example 2
The pranlukast original intermediate N- (3-acetyl-2-hydroxyphenyl) acetamide (F) is prepared as follows:
(a) synthesis of o-acetamidophenol (B)
At the temperature of-5-0 ℃, 110g (1moL) of the compound A is added into 2L of EA solvent, 105mL (1.1moL) of acetic anhydride solution is added in batches, after the addition is finished, the temperature is slowly raised to the room temperature, and the reaction is carried out for 3.5 hours. The reaction mixture was washed with water, brine, dried over anhydrous sodium sulfate and concentrated to give an off-white solid, 150g of a white solid (B) was obtained in a molar yield of 99%.
(b) Synthesis of N- (2-methoxyphenyl) acetamide (C)
60g of compound B and 14g of potassium carbonate were dissolved in 3.5L of DMC at room temperature, and the DMC was refluxed (substrate B and potassium carbonate in a molar ratio of 4:1, 6.26moL of potassium carbonate to 2L of DMC) at a reaction temperature of 90 ℃ with stirring for 4 h. The reaction was checked by thin layer chromatography, after completion of the reaction, the reaction solution was cooled, filtered, the filtrate was slowly poured into 50mL of water, the organic phase was extracted with EA, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give 53.5g of colorless oil C, 81% molar yield.
(c) Synthesis of N- (5-bromo-2-methoxyphenyl) acetamide (D)
Under ice-bath conditions, 26.5g (0.15moL) of NBS, 1L of dichloromethane, and 30.0g (0.20moL) of Compound C were sequentially added to a vessel, and the reaction was carried out under nitrogen atmosphere. After 2.5h of reaction, the reaction was checked by thin layer chromatography, and after completion of the reaction, the organic phase was extracted by adding 7% potassium carbonate solution and dichloromethane and dried over anhydrous magnesium sulfate to give 39.0g of a tan product D in 88% molar yield.
(d) Synthesis of N- (3-acetyl-5-bromo-2-hydroxyphenyl) acetamide (E)
Under ice-bath conditions, 24.4g (0.1moL) of substrate D, 0.5L of dichloromethane, and 13.5g of AlCl were added in this order3(0.10moL) to a reaction flask, 8.5mL (0.12moL) of acetyl chloride was added dropwise, and after stirring for 5 minutes, the reaction was carried out at 25 ℃ under nitrogen. After the reaction was detected to be complete by thin layer chromatography, ice water and dichloromethane were added for extraction, and saturated NaHCO was used sequentially3And brine, and the oil phase was dried over anhydrous sodium sulfate to give 20.4g of reactant E in 75% yield.
(e) Synthesis of N- (3-acetyl-2-hydroxyphenyl) acetamide (F)
Adding 20.0g of reactant E, an ethanol solvent and sodium bicarbonate into a reaction bottle, stirring at room temperature for 0.5h, dissolving and clarifying, adding Pd/C (5%, 0.5g), introducing nitrogen for several minutes to replace air, introducing hydrogen (the gas velocity is controlled to be one bubble per second), raising the temperature to 55 ℃, and reacting for 3.5h, wherein the weight ratio of the reactant E to the Pd/C is 1:0.05, and the mole ratio of the reactant E to an acid-binding agent is: 1:1-3, and the weight ratio of the reactant E to the solvent is 1: 8. Detecting the reaction by using a thin-layer chromatography, stopping introducing air after the reaction is finished, cooling the solution, recovering Pd/C in filter residue, adding a mixture of ethyl acetate and toluene into the filtrate for recrystallization, stirring for 4 hours under a reflux state, filtering while hot, cooling for crystallization, adding water into a filter cake, washing for 3 times, and drying to obtain 10.2g of a target product F, wherein the molar yield is 72.0%, and the purity is 99.8% by HPLC (high performance liquid chromatography).
The total yield of the objective compound, N- (3-acetyl-2-hydroxyphenyl) acetamide (F), was 38.1%.
In conclusion, the scheme protected in example 1 can lead the total yield of the target compound N- (3-acetyl-2-hydroxyphenyl) acetamide (F) to be as high as 41.7 percent and the HPLC purity to be 99.8 percent.
The detection of the target compound N- (3-acetyl-2-hydroxyphenyl) acetamide (F) is as follows:
1H-NMR(500Mz，CDCl3)δ7.98(d,1H)，7.10(q,1H)，7.05(d,1H)，7.23(s,1H)，5.35(s,1H)，2.50(s,3H)，2.04(s,3H)ppm。
it is to be understood that the above description is not intended to limit the present invention, and the present invention is not limited to the above examples, and those skilled in the art may make modifications, alterations, additions or substitutions within the spirit and scope of the present invention.
Claims (6)
1. A preparation method of N- (3-acetyl-2-hydroxyphenyl) acetamide is characterized by comprising the following steps:
the first step is as follows: synthesis of o-acetamidophenol (B)
Dissolving 2-aminophenol (A) in a solvent, dropwise adding acetic anhydride under the ice bath condition, wherein the molar ratio of the 2-aminophenol (A) to the acetic anhydride is 1:1-1.5, the unit millimole of the acetic anhydride corresponds to 2mL of ethyl acetate, after the reaction is completed, sequentially washing a reaction product with water, extracting with ethyl acetate, washing with brine, and drying with anhydrous magnesium sulfate to obtain a compound B, wherein the specific reaction formula is as follows:
the second step is that: synthesis of N- (2-methoxyphenyl) acetamide (C)
Adding o-acetaminophenol (B) and a phase transfer catalyst into a container, adding dimethyl carbonate, reacting under the conditions of heating and refluxing for 3-5 hours to obtain a compound C, wherein the specific reaction formula is as follows:
the third step: synthesis of N- (5-bromo-2-methoxyphenyl) acetamide (D)
Dissolving N- (2-methoxyphenyl) acetamide (C) and NBS in a solvent, reacting for 2-4h in ice bath under the protection of nitrogen to obtain a compound D, wherein the specific reaction formula is as follows:
the fourth step: synthesis of N- (3-acetyl-5-bromo-2-hydroxyphenyl) acetamide (E)
Mixing N- (5-bromo-2-methoxyphenyl) acetamide (D) and AlCl3Dissolving in a solvent, dropwise adding acetyl chloride under the ice bath condition, introducing nitrogen for protection, and reacting for a period of time at normal temperature or at elevated temperature to obtain a compound E, wherein the specific reaction formula is as follows:
the fifth step: synthesis of N- (3-acetyl-2-hydroxyphenyl) acetamide (F)
Adding N- (3-acetyl-5-bromo-2-hydroxyphenyl) acetamide (E) and Pd/C into a solvent, then dropwise adding an acid-binding agent into the solvent in a container, heating and introducing hydrogen, wherein the reaction temperature is 50-75 ℃, and the reaction time is 3-6h, so as to obtain a final product F, and the specific reaction formula is as follows:
2. the process for preparing N- (3-acetyl-2-hydroxyphenyl) acetamide according to claim 1 wherein the phase transfer catalyst is cesium carbonate, potassium carbonate and the reflux temperature is in the range of 95-110 ℃.
3. The process for producing N- (3-acetyl-2-hydroxyphenyl) acetamide according to claim 1, wherein in the third step, the solvent is dichloromethane, ethyl acetate, DMF or chloroform, and after completion of the reaction, 7% potassium carbonate solution and dichloromethane are added for extraction, followed by drying over anhydrous magnesium sulfate.
4. The process for preparing N- (3-acetyl-2-hydroxyphenyl) acetamide according to claim 1 wherein in the fourth step, N- (5-bromo-2-methoxyphenyl) acetamide (D), AlCl3The molar ratio of (1: 1.4) - (1.6), after the reaction is completed, adding ice water and dichloromethane for extraction, and sequentially using saturated NaHCO3The solution was washed with brine and dried over anhydrous sodium sulfate.
5. The process for producing N- (3-acetyl-2-hydroxyphenyl) acetamide according to claim 1 wherein in the fifth step, the acid scavenger is selected from triethylamine, sodium bicarbonate, sodium carbonate, sodium hydroxide or sodium acetate, the weight ratio of N- (3-acetyl-5-bromo-2-hydroxyphenyl) acetamide (E) to Pd/C is 1:0.05-0.2, the molar ratio of N- (3-acetyl-5-bromo-2-hydroxyphenyl) acetamide (E) to acid scavenger is: 1:1-3, wherein the weight ratio of N- (3-acetyl-5-bromo-2-hydroxyphenyl) acetamide (E) to solvent is 1: 5-10; after the reaction is finished, cooling the reaction system, adding a mixture of ethyl acetate and toluene for recrystallization, stirring for a period of time under a reflux state, cooling, adding water to the product for washing, and cooling for crystallization.
6. The process for preparing N- (3-acetyl-2-hydroxyphenyl) acetamide according to claim 1, wherein the product of the first step reaction is added to ethyl acetate as a solvent and purified by recrystallization.
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Citations (3)
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| CN102060731A (en) * | 2010-12-03 | 2011-05-18 | 中国中化股份有限公司 | Method for preparing 2-acetamido-6-acetylphenol |
| CN106588897A (en) * | 2017-02-28 | 2017-04-26 | 上海微巨实业有限公司 | New preparation method of Pranlukast |
| CN107098822A (en) * | 2017-06-07 | 2017-08-29 | 上海微巨实业有限公司 | A kind of preparation method for preparing the hydroxy acetophenone of 3 amino of Pranlukast key intermediate 2 |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102060731A (en) * | 2010-12-03 | 2011-05-18 | 中国中化股份有限公司 | Method for preparing 2-acetamido-6-acetylphenol |
| CN106588897A (en) * | 2017-02-28 | 2017-04-26 | 上海微巨实业有限公司 | New preparation method of Pranlukast |
| CN107098822A (en) * | 2017-06-07 | 2017-08-29 | 上海微巨实业有限公司 | A kind of preparation method for preparing the hydroxy acetophenone of 3 amino of Pranlukast key intermediate 2 |
Non-Patent Citations (1)
| Title |
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| Reexamination of the Thermolytic Rearrangement of 4-Halophenyl Azides to 2-Aminophenols and other Products;H. Gershon等;《Monatshefte fiir Chemie》;19931231;第124卷;第367-379页 * |
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